Pentane-1,5-diol

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2021

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Range Finding

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Remarks:

Range-Finder

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2021

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

14-day dose-range-finding study with determination of water and food consumption, clinical signs, body weights, gross pathology.

GLP compliance:

no

Limit test:

no

Test material

Test material information

1

Reference substance name:

Pentane-1,5-diol

EC Number:

203-854-4

EC Name:

Pentane-1,5-diol

Cas Number:

111-29-5

Molecular formula:

C5H12O2

IUPAC Name:

pentane-1,5-diol

Test material form:

liquid: viscous

Details on test material:

SOURCE OF TEST MATERIAL
- Source and batch number of test material:
- Expiration date of the batch:
- Purity:
- Purity test date:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
-The stability, homogeneity and the concentration of the test substance preparations will not be verified analytically in this study.

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Crl:WI(Han)

Details on species / strain selection:

The rat was chosen as the test species because it is accepted by regulatory agencies. The Han Wistar [RccHan®:WIST] strain was used because of the historical control data available at this laboratory

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Envigo RMS Limited
- Age at study initiation: 83 to 89 days
- Weight at study initiation: male: (312 to 339 g), female: (200 to 215 g)
- Housing: 3 animals per cage
- Diet (e.g. ad libitum): SDS VRF1 Certified, pelleted diet.
- Water (e.g. ad libitum): Potable water from the public supply.
- Acclimation period: From delivery to the beginning of administration the animals will be accustomed to the environmental conditions and to the diet.

DETAILS OF FOOD AND WATER QUALITY:
The food used in the study will be assayed for chemical and microbial contaminants. Fed. Reg.Vol. 44, No. 91 (09 May1979), p 27354 (EPA), will serve as the guideline for maximum tolerable contaminants. Additionally the levels of phytoestrogens should not exceed 350 μg ofgenistein equivalents/gram. According to recommendations of the GVSOLAS, the total amount of bacteria must not exceed 1*10^5/g food. The drinking water is regularly assayed for chemical contaminants both by the municipal authorities of Frankenthal and by the Environmental Analytics Water/Steam Monitoring Department of BASF SE as weil as for bacteria by a contract laboratory. The Drinking Water Regulation will serve as the guideline for maximum tolerable contaminants.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 40-70%
- Photoperiod: 12 hrs dark / 12 hrs light

Administration / exposure

Route of administration:

oral: gavage

Details on route of administration:

The oral route was selected since this was proven to be suitable for the detection of a toxicological hazard.

Vehicle:

water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
Method of preparation: The formulation procedure will be documented in the study data and included in the final report. The required amount of test item will be ground in a mortar using a pestle and mixed with some vehicle to form a paste. Further amounts of vehicle will be gradually added and mixed to produce a smooth, pourable suspension. The suspension will be quantitatively transferred and diluted to volume and finally mixed using a high-shear homogeniser. A series of suspensions/formulations at the required concentrations will be prepared by dilution of individual weighings of the test item.
Frequency of preparation Weekly, and may be prepared in advance of the first day of dosing.

VEHICLE
Method of preparation The required amount of test item was weighed and approximately 80% of the final volume of vehicle was added. This was magnetically stirred until uniformly mixed and made up to the required volume with the vehicle, followed by further magnetic stirring until homogeneous. Method of preparation The required amount of test item was weighed and approximately 80% of the final volume of vehicle was added. This was magnetically stirred until uniformly mixed and made up to the required volume with the vehicle, followed by further magnetic stirring until homogeneous.
Frequency of preparation: Weekly

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

No analysis of the test-substance preparations will be carried out in the present study.

Duration of treatment / exposure:

2 weeks

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

Doses / concentrations 2

Dose / conc.:

300 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

3

Control animals:

yes, concurrent vehicle

Details on study design:

The purpose of this study was to make a preliminary assessment of the systemic toxic potential of 1, 5 Pentanediol, an industrial chemical, when administered orally, by gavage, to Han Wistar rats for 14 days. The results of this study were used to select a suitable high dose for a subsequent OECD 422 screening study. Two groups, each comprising four male and four female Han Wistar rats, received 1, 5 Pentanediol at doses of 300 or 1000 mg/kg/day. A similarly constituted control group received the vehicle, purified water, at the same volume dose as the treated groups. During the study, clinical condition, body weight, food consumption, visual water consumption, hematology (peripheral blood), blood chemistry, organ weight and macropathology investigations were undertaken.

Positive control:

no

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS:
Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. Cages were inspected daily for evidence of animal ill-health amongst the occupants. Any deviation from normal was recorded at the time in respect of nature and severity, date and time of onset, duration and progress of the observed condition, as appropriate. During the acclimatization period, observations of the animals and their cages were recorded at least once per day.

DETAILED CLINICAL OBSERVATIONS:
Detailed clinical observations (DCO) will be performed in all animals prior to the administration period and thereafter at weekly intervals. The following parameters will be examined: abnormal behavior during “handling”, fur, skin, posture, salivation, respiration, activity/arousal level, tremors, convulsions, abnormal movements, gait abnormalities, lacrimation, palpebral closure, exophthalmus, feces (appearance/consistency), urine, pupil size

BODY WEIGHT:
The weight of each animal was recorded three days before treatment commenced, on the day that treatment commenced (Day 1), on Days 4, 8, 11 and 15 (before necropsy).

FOOD CONSUMPTION:
The weight of food supplied to each animal, that remaining and an estimate of any spilled was recorded for the three days before treatment commenced and on Days 1-4, 4-8, 8-11 and 11-15 of treatment.

FOOD EFFICIENCY:No

WATER CONSUMPTION:
Fluid intake was assessed by daily visual observation. No effect was observed and, consequently, quantitative measurements were not performed.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY:
Animals were held under light general anesthesia induced by isoflurane. Blood samples (nominally 0.5 mL) were withdrawn from the sublingual vein, collected into tubes containing EDTA anticoagulant and examined for the following characteristics using a Bayer Advia 120 analyzer:
 Hematocrit (Hct)*
 Hemoglobin concentration (Hb)
 Erythrocyte count (RBC)
 Absolute and relative reticulocyte count (Retic)
 Mean cell hemoglobin (MCH)*
 Mean cell hemoglobin concentration (MCHC)*
 Mean cell volume (MCV)
 Red cell distribution width (RDW)
 Total leucocyte count (WBC)
 Differential leucocyte count:
 Neutrophils (N)
 Lymphocytes (L)
 Eosinophils (E)
 Basophils (B)
 Monocytes (M)
 Large unstained cells (LUC)
 Platelet count (Plt)
* Derived values calculated in ClinAxys
 Prothrombin time (PT) - using IL PT Fibrinogen reagent.
 Activated partial thromboplastin time (APTT) - using IL APTT reagent.

CLINICAL CHEMISTRY:
Animals were held under light general anesthesia induced by isoflurane. Blood samples (nominally 0.7 mL) were withdrawn from the sublingual vein and collected into tubes containing lithium heparin as anticoagulant. After separation, the plasma was examined using a Roche Cobas 6000 Analyzer in respect of:

a Roche Cobas 6000 Analyzer in respect of:
 Alkaline phosphatase (ALP)
 Alanine aminotransferase (ALT)
 Aspartate aminotransferase (AST)
 Gamma-glutamyl transferase (gGT)
 Total bilirubin (Bili)
 Bile acids (Bi Ac)
 Urea
 Creatinine (Creat)
 Glucose (Gluc)
 Total cholesterol (Chol)
 Triglycerides (Trig)
 Sodium (Na)
 Potassium (K)
 Chloride (Cl)
 Calcium (Ca)
 Inorganic phosphorus (Phos)
 Total protein (Total Prot)
 Albumin (Alb)
Albumin/globulin ratio (A/G Ratio) was calculated from total protein concentration and
analyzed albumin concentration.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
Organ weights are not routinely recorded for animals killed or dying prematurely; organ weights will be recorded for groups terminated prematurely.
All paired organs will be weighted together (left and right).: Adrenal glands , Kidneys, Liver, Spleen

HISTOPATHOLOGY: No

Statistics:

Means and standard deviations will be calculated. In addition, the following statistical analyses will be carried out:
- for body weight and body weight change: DUNNETT'S (two-sides)

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

There were no treatment-related clinical signs and no animals died during the study.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

Overall body weight gain (Day 1-15) was 38% lower than control in females receiving 1000 mg/kg/day. However, this corresponded to only a 7 g difference in final body weights. In contrast, males receiving 1000 mg/kg/day gained slightly more weight than the controls (21% higher). There was considered to be no effect on body weight gain in both sexes receiving 300 mg/kg/day.

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

Overall food intake (Day 1-15) was lower 11% than controls in females receiving 1000 mg/kg/day. Food intake was unaffected in females receiving 300 mg/kg/day and at all doses in males.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

The hematological examination performed after 14 days of treatment revealed, compared with controls, slightly higher neutrophil, lymphocyte and, consequently, total leucocyte counts in both sexes receiving 1000 mg/kg/day and in males receiving 300 mg/kg/day. Basophil, monocyte and large unstained cell counts were also slightly higher than controls in males receiving 300 or 1000 mg/kg/day but were unaffected in females. All other inter-group differences, including those attaining statistical significance, were minor or lacked dose-relationship and were attributed to normal biological variation. Such differences included the low hematocrit in both sexes receiving 300 or 1000 mg/kg/day, which were statistically significant in males, and were associated with marginal decreases of hemoglobin concentration and erythrocyte count and marginal increases of mean cell hemoglobin and mean cell volume in males only, where the difference from control was marginal.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

The biochemical examination of the blood plasma performed after 14 days of treatment revealed, when compared with controls, slightly higher plasma total cholesterol and triglyceride concentrations in males receiving 300 or 1000 mg/kg/day, although statistical significance was not attained, and females were unaffected. Plasma urea concentration was slightly higher than control in females receiving 300 or 1000 mg/kg/day, with statistical significance being attained at the high dose only. In males, urea concentration was only marginally higher than control in males at these dose levels and there was no dose-response. All other inter-group differences, including those attaining statistical significance, were minor or lacked dose-relationship and were attributed to normal biological variation. Such differences included the statistically significantly low phosphorus concentration in males receiving 300 or 1000 mg/kg/day, where there was no dose-relationship. They also included the high bile acid concentration in females receiving 1000 mg/kg/day, which was attributed to one individual with a particularly high value (No. 110; 46.0 µmol/L). Creatinine was statistically significantly low in males receiving 300 mg/kg/day but was unaffected at 1000 mg/kg/day and, as such, this was not attributable to treatment. Albumin to globulin ratio was statistically significantly low in males receiving 300 or 1000 mg/kg/day, but there was no dose-response, as the lowest group mean value occurred at 300 mg/kg/day.

Endocrine findings:

not examined

Urinalysis findings:

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

The analysis of organ weights performed after 14 days of treatment revealed, compared with controls, slightly higher absolute and body weight-adjusted liver weight and body weight-adjusted kidney weight in females receiving 1000 mg/kg/day. The difference in adjusted liver weights and kidney weights was 12% and 11%, respectively. In males, absolute and body weight-adjusted liver weights were higher than control at 300 or 1000 mg/kg/day, but there was no dose-response. Kidney weights were unaffected in males. All other intergroup differences were minor or lacked dose relationship and, as such, were attributed to natural biological variation.

Neuropathological findings:

not examined

Histopathological findings: neoplastic:

no effects observed

Other effects:

effects observed, non-treatment-related

Description (incidence and severity):

The macroscopic examination performed after 14 days of treatment revealed no treatment-related findings.

Applicant's summary and conclusion

Conclusions:

It is concluded that, in the absence of any dose-limiting test item-related effects in this 14-day toxicity study, a dose level of 1000 mg/kg/day would be suitable for use as the high dose level in the subsequent OECD422 main study.

Executive summary:

The oral administration of 1, 5 Pentanediol to Han Wistar rats for 14 days was clinically well-tolerated, with no treatment-related clinical signs and no premature death. Body weights were comparable between the groups. Overall mean body weight gain in females receiving 1000 mg/kg/day was 38% lower than control (associated with an 11% reduction of overall food intake) however this represented a difference of only 7 grams when compared to controls and was therefore considered not to be dose limiting. There was no similar finding in males, where overall weight gain was higher than control at 1000 mg/kg/day. Slightly higher adjusted liver and kidney weights were observed in females at 1000 mg/kg/day. The increased kidney weights may be associated with the higher plasma urea concentration observed in females receiving 300 or 1000 mg/kg/day. There were slight increases of leucocyte subpopulations in both sexes receiving 1000 mg/kg/day and in males receiving 300 mg/kg/day (mainly neutrophil and lymphocyte counts, with basophil and monocyte counts also being slightly higher in males) but the cause was unclear. The extent of the differences were considered not to be dose-limiting.